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Wei WH, Bai YL, Zhu D, Zhang JY, Yin QC, Li Q, Shen CQ, Jin PS. Dl-3-n-butylphthalide ameliorates diabetic foot ulcer by inhibiting apoptosis and promoting angiogenesis. World J Diabetes 2025; 16:101916. [DOI: 10.4239/wjd.v16.i4.101916] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 12/10/2024] [Accepted: 01/21/2025] [Indexed: 02/28/2025] Open
Abstract
BACKGROUND Diabetic foot ulcers (DFU) are estimated to affect about 18.6 million people worldwide annually. The pathogenesis of DFU is complex, and the available drugs are not effective. Dl-3-n-butylphthalide (NBP) is a synthetic mixture of racemates used in China for the treatment of ischemic stroke. It was initially isolated from the seeds of Apium graveolens Linn, with studies showing its potential role in treating diabetes and its complications.
AIM To predict and validate the mechanism by which NBP treats DFU.
METHODS Network pharmacological analysis was performed to identify pharmacological targets and signaling pathways mediating the treatment effect of NBP on DFU. In vivo and in vitro experiments were conducted to validate the therapeutic effects and mechanisms of NBP on DFU.
RESULTS Network pharmacology analysis identified 26 pharmacological targets of NBP and predicted that NBP could treat DFU partially by modulating apoptosis and vascular signaling pathways. Results from animal experiments showed that NBP significantly improved DFU by increasing neovascularization and fibroblast proliferation. In vitro tests demonstrated that NBP treatment promoted the migration and proliferation of human umbilical vein endothelial cells and human dermal fibroblasts, while inhibiting the apoptosis of human umbilical vein endothelial cells, human dermal fibroblasts, and human keratinocytes cells.
CONCLUSION This study found that NBP could treat DFU by decreasing the rate of apoptosis and increasing angiogenesis via the advanced glycation end products-receptor of advanced glycation end products signaling pathway and binding to the heme oxygenase 1, caspase 3, B cell leukemia/lymphoma 2, brain derived neurotrophic factor, and nuclear factor erythroid 2 L2 genes.
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Affiliation(s)
- Wu-Han Wei
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100144, China
| | - Yuan-Ling Bai
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Dong Zhu
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Jing-Yu Zhang
- The First Clinical Medical College, Xuzhou Medical University, Xuzhou 221004, Jiangsu Province, China
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Qi-Chuan Yin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Qiang Li
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Cai-Qi Shen
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
| | - Pei-Sheng Jin
- Department of Plastic Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221006, Jiangsu Province, China
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2
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Soda T, Pasqua T, De Sarro G, Moccia F. Cognitive Impairment and Synaptic Dysfunction in Cardiovascular Disorders: The New Frontiers of the Heart-Brain Axis. Biomedicines 2024; 12:2387. [PMID: 39457698 PMCID: PMC11504205 DOI: 10.3390/biomedicines12102387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 10/13/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Within the central nervous system, synaptic plasticity, fundamental to processes like learning and memory, is largely driven by activity-dependent changes in synaptic strength. This plasticity often manifests as long-term potentiation (LTP) and long-term depression (LTD), which are bidirectional modulations of synaptic efficacy. Strong epidemiological and experimental evidence show that the heart-brain axis could be severely compromised by both neurological and cardiovascular disorders. Particularly, cardiovascular disorders, such as heart failure, hypertension, obesity, diabetes and insulin resistance, and arrhythmias, may lead to cognitive impairment, a condition known as cardiogenic dementia. Herein, we review the available knowledge on the synaptic and molecular mechanisms by which cardiogenic dementia may arise and describe how LTP and/or LTD induction and maintenance may be compromised in the CA1 region of the hippocampus by heart failure, metabolic syndrome, and arrhythmias. We also discuss the emerging evidence that endothelial dysfunction may contribute to directly altering hippocampal LTP by impairing the synaptically induced activation of the endothelial nitric oxide synthase. A better understanding of how CV disorders impact on the proper function of central synapses will shed novel light on the molecular underpinnings of cardiogenic dementia, thereby providing a new perspective for more specific pharmacological treatments.
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Affiliation(s)
- Teresa Soda
- Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy; (T.P.); (G.D.S.)
| | - Teresa Pasqua
- Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy; (T.P.); (G.D.S.)
| | - Giovambattista De Sarro
- Department of Health Sciences, University of Magna Graecia, 88100 Catanzaro, Italy; (T.P.); (G.D.S.)
| | - Francesco Moccia
- Department of Medicine and Health Sciences “V. Tiberio“, University of Molise, 86100 Campobasso, Italy;
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Ma Y, Guo C, Wang Y, Liu X. Effects of Dl-3-n-butylphthalide on neurological function, hemodynamics and Hcy concentration in cerebral hemorrhage: a systematic review and meta-analysis. Front Pharmacol 2024; 15:1360932. [PMID: 38881880 PMCID: PMC11177091 DOI: 10.3389/fphar.2024.1360932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/06/2024] [Indexed: 06/18/2024] Open
Abstract
Background Dl-3-n-Butylphthalide (NBP) has emerged as a potential therapeutic agent for cerebral hemorrhage, despite not being included in current guideline recommendations. Investigating the underlying physiological and pathological mechanisms of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment remains a critical area of research. Objective This review aims to evaluate the efficacy of Dl-3-n-Butylphthalide in cerebral hemorrhage treatment and elucidate its potential biological mechanisms, thereby providing evidence to support treatment optimization. Methods A comprehensive search of seven electronic databases (PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure, VIP, and Wanfang Database) was conducted for studies published up to September 2023. Screening and data extraction were performed by a team of researchers. The Cochrane collaboration tool was utilized for risk bias assessment, and Revman 5.3 along with Stata 17.0 were employed for statistical analysis. Outcomes We searched 254 literature, and 19 were included in this meta-analysis. The results showed that Dl-3-n-Butylphthalide improved the clinical efficacy rate (RR = 1.25, 95% CI 1.19-1.31; p = 0.00), quality of life (MD = 13.93, 95% CI: 11.88-15.98; p = 0.000), increased cerebral blood flow and velocity, reduced cerebral edema volume, Hcy concentration, and did not have obvious adverse reactions (RR = 0.68, 95% CI: 0.39-1.18; p = 0.10). Conclusion This meta-analysis is the first to demonstrate the potential of Dl-3-n-Butylphthalide in treating cerebral hemorrhage. It suggests that Dl-3-n-Butylphthalide may alleviate clinical symptoms by modulating neurological function and improving hemodynamics. Our findings provide robust evidence for incorporating Dl-3-n-Butylphthalide into cerebral hemorrhage treatment strategies, potentially guiding future clinical practice and research. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ display_record.php?RecordID=355114, Identifier CRD42022355114.
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Affiliation(s)
- Yingqi Ma
- First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China
| | - Chenchen Guo
- Neck-Shoulder and Lumbocrural Pain Hospital of Shandong First Medical University, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yiguo Wang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinxin Liu
- Centre for Evidence-Based Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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4
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Ma B, Li Q, Li M, Wang J, Fan N, Yang S, Shi W, Wang R, Yin D. Effect of butylphthalide on prevention and treatment of high altitude cerebral edema in rats. Heliyon 2024; 10:e27833. [PMID: 38560678 PMCID: PMC10979156 DOI: 10.1016/j.heliyon.2024.e27833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 03/05/2024] [Accepted: 03/07/2024] [Indexed: 04/04/2024] Open
Abstract
3-n-butylphthalide (NBP) contains one of the main active ingredients of celery seed. It has a series of pharmacological mechanisms, including reconstitution of microcirculation, protection of mitochondrial function, inhibition of oxidative stress, and inhibition of neuronal apoptosis. Based on the complex multi-targeting of NBP pharmacological mechanisms, the clinical applications of NBP are increasing, and more and more clinical studies and animal experiments have focused on NBP. In this study, we used male Sprague Dawley rats as an animal model to elucidate the intervention effect of butylphthalide on high altitude cerebral edema (HACE), and also compared the effect of butylphthalide and rhodiola rosea on HACE. Firstly, we measured the changes of body weight and brain water content and observed the pathological changes of brain tissues. In addition, the contents of inflammatory factors, oxidative stress and brain neurotransmitters were assessed by enzyme-linked immunoassay kits, and finally, the expression of apoptotic proteins in brain tissues was determined by western blotting. The results showed that NBP reduced brain water content, attenuated brain tissue damage, altered inflammatory factors, oxidative stress indicators, and brain neurotransmitter levels, and in addition NBP inhibited the expression of Caspase-related apoptotic proteins. Therefore, NBP has the potential to treat and prevent HACE.
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Affiliation(s)
- Bohua Ma
- Department of Pharmacy, Qingyang People's Hospital, Qingyang City, Gansu Province, China
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Qian Li
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Meng Li
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Jiangtao Wang
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Ning Fan
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Shanpeng Yang
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Wenhui Shi
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Rui Wang
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
| | - Dongfeng Yin
- Department of Pharmacy, General Hospital of Xin- jiang Military Region, Urumqi, Xinjiang, China
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Xu W, Wang X, Hou X, Yang Y, Ma R, Lv R, Yin Q. The role of microglia in the pathogenesis of diabetic-associated cognitive dysfunction. Front Endocrinol (Lausanne) 2024; 14:1246979. [PMID: 38274227 PMCID: PMC10808430 DOI: 10.3389/fendo.2023.1246979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 12/29/2023] [Indexed: 01/27/2024] Open
Affiliation(s)
- Wenwen Xu
- Department of Ophthalmology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xinyu Wang
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Xunyao Hou
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Yan Yang
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Rongrong Ma
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Renjun Lv
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Qingqing Yin
- Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China
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Benchoula K, Mediani A, Hwa WE. The functions of Ca 2+/calmodulin-dependent protein kinase II (CaMKII) in diabetes progression. J Cell Commun Signal 2023; 17:25-34. [PMID: 35551607 PMCID: PMC10030766 DOI: 10.1007/s12079-022-00680-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/14/2022] [Indexed: 11/30/2022] Open
Abstract
The increase in blood glucose causes a myriad of pathways and molecular components to malfunction, leading to diabetes. Diabetes affects each organ differently by activating distinct pathways. It has an impact on the liver, pancreas, kidney (nephropathy), eyes (retinopathy), and nervous system (neuropathy). Understanding the effects of diabetes on each organ is the first step in developing a sustained treatment for the disease. Among the many cellular molecules impacted by diabetes is Ca2+/calmodulin-dependent protein kinase II (CaMKII), a complex Ca2+/calmodulin-activated serine/threonine-protein kinase. When intracellular [Ca2+] rises, it binds to calmodulin (CaM) to produce Ca2+/CaM, which activates CaMKIIs. This factor is involved in the pancreas, liver, heart, muscles, and various organs. Thus, Understanding CaMKII action in each organ is critical for gaining a complete picture of diabetic complications. Therefore, this review covers CaMKII's functions in many organs and how it affects and has been affected by diabetes.
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Affiliation(s)
- Khaled Benchoula
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia
| | - Ahmed Mediani
- Institute of Systems Biology (INBIOSIS), University Kebangsaan Malaysia, 43600, Bangi, Selangor, Malaysia
| | - Wong Eng Hwa
- School of Medicine, Faculty of Health and Medical Sciences, Taylor's University, 1, Jalan Taylors, 47500, Subang Jaya, Selangor, Malaysia.
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He J, Gao J, Zhu H, Zhao Y, Zhang X, Wang X, Wan S, Cao H, Zhai L, Wang Y, Wang S. Effects of NBP on postoperative cognitive dysfunction in rats via Nrf 2/ARE pathway. Aging (Albany NY) 2023; 15:276-286. [PMID: 36626245 PMCID: PMC9876636 DOI: 10.18632/aging.204481] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 12/29/2022] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Postoperative cognitive dysfunction (POCD) is a common postoperative disease that threatens patients' quality of life, especially elderly patients. With the popularity of anesthesia/surgery, POCD has received more attention worldwide. The objective of this research is to evaluate 3-n-Butylphthalide (NBP)'s protective effect on postoperative cognitive function in rats and its related mechanisms. METHODS Tibial fracture models of senile rats of POCD were established and divided into blank control group, solvent group, NBP group, Nrf 2 agonist group, and Nrf 2 inhibitor group. The changes in the cognitive abilities of rats were systematically evaluated by the Morris water maze test. After hematoxylin-eosin (HE) staining of the hippocampus, the morphological and structural changes of hippocampal neurons were observed by light microscopy. The expressions of apoptosis-related proteins were analyzed by immunohistochemistry and Western blot was used to detect the expressions of Nrf 2,HO-1,Mfn1,Mfn2,Drp1 proteins. Moreover, the changes in the morphology of mitochondria were observed by transmission electron microscopy. RESULTS Through the water maze test, we observed that the incidence of postoperative cognitive impairment in the NBP, agonist, and inhibitor groups was substantially lower as compared to the blank control group and solvent group (P < 0.05). The expressions of Nrf 2, HO-1, Mfn1, Mfn2, and Drp1 proteins in the NBP group were upregulated in comparison to the blank control group and the solvent group. The expressions of related proteins in the inhibitor group were substantially lower in comparison to the NBP group. CONCLUSIONS NBP can affect the postoperative cognitive function of rats by activating the Nrf 2/ARE signaling pathway.
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Affiliation(s)
- Jianshuai He
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Junqiong Gao
- Department of Anesthesiology, Weihai Municipal Hospital, Weihai, China
| | - He Zhu
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yang Zhao
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaotian Zhang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiufang Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shengnan Wan
- Department of Thyroid Surgery, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Hongying Cao
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lin Zhai
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yuanyong Wang
- Department of Thoracic Surgery, Tangdu Hospital of Air Force Military Medical University, Xi’an, China
| | - Shilei Wang
- Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, China
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Chen J, Xiao L, Chen Y, Li W, Liu Y, Yi F, Zhou Y, Tan H. Butylphthalide alleviates sleep deprivation-induced cognitive deficit by regulating Nrf2/HO-1 pathway. Sleep Med 2022; 100:427-433. [PMID: 36244317 DOI: 10.1016/j.sleep.2022.09.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 01/12/2023]
Abstract
PURPOSE The purpose of this study was to assess the effects of butylphthalide on cognitive deficiencies following sleep deprivation (SD). METHODS The influence of butylphthalide on cognitive function changes in SD-induced mice was evaluated. Nissl staining and HE staining were used to analyze the morphology changes of the hippocampal formation. The changes in cognitive function of SD-induced mice were detected by the Morris water maze. Inflammatory factors, apoptosis, and signal pathway-related proteins in the mice hippocampus were detected. RESULTS SD increased escape latency and path length for mice to reach the hidden platform, decreased the time and range of activity in the target area, and reduced the number and time for traversing the target area. Butylphthalide significantly improved the cognitive decline of SD-induced spatial exploration and learning/memory ability. Butylphthalide also decreased the degeneration of hippocampal neurone, neuronal apoptosis, and inflammatory factors in hippocampus tissue. In addition, butylphthalide activated the nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase 1 (HO-1) pathway. CONCLUSION Butylphthalide alleviated SD-induced cognitive decline, neuronal apoptosis, and inflammation by activating Nrf2/HO-1 pathway. We suggested that butylphthalide may be a prospective candidate for the alleviation of cognitive deficit induced by SD.
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Affiliation(s)
- Juan Chen
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China.
| | - Lijun Xiao
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Ying Chen
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Wei Li
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Yinan Liu
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Fang Yi
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Ying Zhou
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
| | - Hong Tan
- Department of Neurology, The First Hospital of Changsha, Changsha City, HuNan Province, 410005, China
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Tan SW, Xie T, Malik TH, Gao Y. Advances of neurovascular protective potential of 3-N-butylphthalide and its derivatives in diabetic related diseases. J Diabetes Complications 2022; 36:108335. [PMID: 36240669 DOI: 10.1016/j.jdiacomp.2022.108335] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/18/2022] [Accepted: 10/01/2022] [Indexed: 11/20/2022]
Abstract
3-N-butylphthalide (NBP) is a component isolated from seeds of Chinese celery, and it was firstly approved for the treatment of ischemic stroke. With the gradual in-depth understanding of its pharmacological action, it was found that it may have potential effects on treating diabetes and its complications. This review aims to illustrate the researches on the properties of NBP and its therapeutic efficacy in diabetic related diseases. This review will discuss the results of experiments in vitro and in vivo to make progress in understanding the beneficial effects of NBP and its derivatives on diabetic complications including diabetic vascular diseases, diabetic peripheral neuropathy, diabetic brain related diseases and diabetic cataract. We will also demonstrate NBP's numerous molecular targets and interactions with multiple cellular signaling pathways such as oxidative stress, inflammatory responses, apoptosis and autophagy. NBP is proved to be a potential therapeutic approach for treating diabetic complications.
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Affiliation(s)
- Shu-Wen Tan
- Department of Endocrinology, The First Hospital of Jilin University, Jilin, China
| | - Tian Xie
- Department of Neurosurgery, The People's Hospital of Jilin Province, Jilin, China
| | | | - Ying Gao
- Department of Endocrinology, The First Hospital of Jilin University, Jilin, China.
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CaMKIIα Signaling Is Required for the Neuroprotective Effects of Dl-3-n-Butylphthalide in Alzheimer's Disease. Mol Neurobiol 2022; 59:3370-3381. [PMID: 35305243 DOI: 10.1007/s12035-022-02777-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 02/15/2022] [Indexed: 10/18/2022]
Abstract
Alzheimer's disease (AD) is the most common form of neurodegenerative disease and most anti-AD drugs have failed in clinical trials; hence, it is urgent to find potentially effective drugs against AD. DL-3-n-butylphthalide (NBP) is a compound extracted from celery seed and is a multiple-target drug. Several studies have demonstrated the neuroprotective effects of NBP on cognitive impairment, but the mechanisms of NBP remains relatively unexplored. In this study, we found that NBP could alleviated the increase of intracellular Ca2+ and reversed down-regulation of Ca2+/calmodulin-dependent protein kinase alpha (CaMKIIα) signaling and rescued neuronal apoptosis in SH-SY5Y cells treated by Aβ oligomers. However, these neuroprotective effects of NBP on neuronal damage and CaMKIIα signaling were abolished when CaMKIIα expression was knocked down or its activity was inhibited. Thus, our findings suggested that CaMKIIα signaling was required for the neuroprotective effects of NBP in AD and provided an improved basis for elucidating the mechanism and treatment of NBP in AD.
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Ma S, Bi W, Liu X, Li S, Qiu Y, Huang C, Lv R, Yin Q. Single-Cell Sequencing Analysis of the db/db Mouse Hippocampus Reveals Cell-Type-Specific Insights Into the Pathobiology of Diabetes-Associated Cognitive Dysfunction. Front Endocrinol (Lausanne) 2022; 13:891039. [PMID: 35721719 PMCID: PMC9200615 DOI: 10.3389/fendo.2022.891039] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/27/2022] [Indexed: 11/13/2022] Open
Abstract
Diabetes-associated cognitive decline (DCD), is one of the complications of diabetes, which is characterized by a series of neurophysiological and pathological abnormalities. However, the exact pathogenesis of DCD is still unknown. Single-cell RNA sequencing (scRNA-seq) could discover unusual subpopulations, explore functional heterogeneity and identify signaling pathways and potential markers. The aim of this research was to provide deeper opinion into molecular and cellular changes underlying DCD, identify different cellular types of the diabetic mice hippocampus at single-cell level, and elucidate the factors mediating the pathogenesis of DCD. To elucidate cell specific gene expression changes in the hippocampus of diabetic encephalopathy. Single-cell RNA sequencing of hippocampus from db/m and db/db mice was carried out. Subclustering analysis was performed to further describe microglial cell subpopulations. Interestingly using immunohistochemistry, these findings were confirmed at the protein level. Single cell analysis yielded transcriptome data for 14621 hippocampal cells and defined 11 different cell types. Analysis of differentially expressed genes in the microglia compartments indicated that infection- and immune system process- associated terms, oxidative stress and inflammation play vital roles in the progression of DCD. Compared with db/m mouse, experiments at the protein level supported the activation of microglia, increased expression of inflammatory factors and oxidative stress damage in the hippocampus of db/db mouse. In addition, a major finding of our research was the subpopulation of microglia that express genes related to pro-inflammatory disease-associated microglia (DAM). Our research reveals pathological alterations of inflammation and oxidative stress mediated hippocampal damage in the db/db mice, and may provide potential diagnostic biomarkers and therapeutic interventions for DCD.
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Affiliation(s)
- Shizhan Ma
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wenkai Bi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xueying Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shangbin Li
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yaxin Qiu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chengcheng Huang
- Clinical Education Administration, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Renjun Lv
- Department of Geriatrics, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Renjun Lv, ; Qingqing Yin,
| | - Qingqing Yin
- Department of Geriatric Neurology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- *Correspondence: Renjun Lv, ; Qingqing Yin,
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Yang S, Yu C, Yang Z, Cui H, Wu Y, Liang Z, Liu Y, Shi X, Shao F, Zhao S, Tang Z. DL-3-n-butylphthalide-induced neuroprotection in rat models of asphyxia-induced cardiac arrest followed by cardiopulmonary resuscitation. J Cell Physiol 2021; 236:7464-7472. [PMID: 34061993 DOI: 10.1002/jcp.30442] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 05/09/2021] [Accepted: 05/11/2021] [Indexed: 12/20/2022]
Abstract
Most patients that resuscitate successfully from cardiac arrest (CA) suffer from poor neurological prognosis. DL-3-n-butylphthalide (NBP) is known to have neuroprotective effects via multiple mechanisms. This study aimed to investigate whether NBP can decrease neurological impairment after CA. We studied the protective role of NBP in the hippocampus of a rat model of cardiac arrest induced by asphyxia. Thirty-nine rats were divided randomly into sham, control, and NBP groups. Rats in control and NBP groups underwent cardiopulmonary resuscitation (CPR) 6 min after asphyxia. NBP or vehicle (saline) was administered intravenously 10 min after the return of spontaneous circulation (ROSC). Ultrastructure of hippocampal neurons was observed under transmission electron microscope. NBP treatment improved neurological function up to 72 h after CA. The ultrastructural lesion in mitochondria recovered in the NBP-treated CA model. In conclusion, our study demonstrated multiple therapeutic benefits of NBP after CA.
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Affiliation(s)
- Song Yang
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Emergency Medicine, Beijing Huairou Hospital, Beijing, China
| | - Changxiao Yu
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhengfei Yang
- Department of Emergency Medicine, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hao Cui
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Yang Wu
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Zhen Liang
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Ying Liu
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Xian Shi
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Department of Emergency Medicine, Beijing Huairou Hospital, Beijing, China
| | - Fei Shao
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
| | - Shen Zhao
- Department of Emergency Medicine, Fujian Provincial Hospital, Fujian Institute of Emergency Medicine, Fujian Medical University, Fuzhou, China
| | - Ziren Tang
- Department of Emergency Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chaoyang Hospital, Beijing, China
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Zheng B, Jin Y, Mi S, Xu W, Yang X, Hong Z, Wang Z. Dl-3-n-butylphthalide Attenuates Spinal Cord Injury via Regulation of MMPs and Junction Proteins in Mice. Neurochem Res 2021; 46:2297-2306. [PMID: 34086144 DOI: 10.1007/s11064-021-03361-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/13/2021] [Accepted: 05/24/2021] [Indexed: 10/21/2022]
Abstract
As a serious trauma of the neurological system, spinal cord injury (SCI) results in permanent disability, gives rise to immediate vascular damage and a wide range of matters that induce the breakage of blood spinal cord barrier (BSCB). SCI activates the expression of MMP-2/9, which are considered to accelerate the disruption of BSCB. Recent research shows that Dl-3-n-butylphthalide (NBP) exerted protective effects on blood spinal cord barrier in animals after SCI, but the underlying molecular mechanism of NBP on the BSCB undergoing SCI is unknown. Here, our research show that NBP inhibited the expression of MMP-2/9, then improved the permeability of BSCB following SCI. After the T9 level of spinal cord performed with a moderate injury, NBP was managed by intragastric administration and further performed once a day. NBP remarkably improved the permeability of BSCB and junction proteins degration, then promoted locomotion recovery. The protective effect of NBP on BSCB destruction is related to the regulation of MMP-2/9 induced by SCI. Moreover, NBP obviously inhibited the MMP-2/9 expression and junction proteins degradation in microvascular endothelial cells. In conclusion, our results indicate that MMP-2/9 are relevant to the breakdown of BSCB, NBP impairs BSCB destruction through inhibiting MMP-2/9 and promotes functional recovery subjected to SCI. NBP is likely to become a new nominee as a therapeutic to treat SCI via a transigent BSCB.
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Affiliation(s)
- Binbin Zheng
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China
| | - Yanjun Jin
- Nursing Department, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China
| | - Shuang Mi
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China
| | - Wei Xu
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China
| | - Xiangdong Yang
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China
| | - Zhenghua Hong
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China.
| | - Zhangfu Wang
- Department of Orthopaedics, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Linhai, 317000, Zhejiang, People's Republic of China.
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14
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Zhou Y, Xu B, Yu H, Zhao W, Song X, Liu Y, Wang K, Peacher N, Zhao X, Zhang HT. Biochanin A Attenuates Ovariectomy-Induced Cognition Deficit via Antioxidant Effects in Female Rats. Front Pharmacol 2021; 12:603316. [PMID: 33815102 PMCID: PMC8010695 DOI: 10.3389/fphar.2021.603316] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/19/2021] [Indexed: 01/05/2023] Open
Abstract
Background: Impairment of memory and cognition is one of the major symptoms in women with postmenopausal disorders due to estrogen deficiency, which accounts for the much higher prevalence of Alzheimer’s disease in females. Biochanin A (BCA), a natural phytoestrogen, has been reported to protect neurons against ischemic brain injury. However, the neuroprotective effects of BCA in the postmenopausal-like model of ovariectomized (OVX) rats remain to be investigated. Methods: All the rats except for the sham group underwent the resection of bilateral ovaries. Seven days after the OVX surgery, rats were randomly divided into six groups: sham, OVX, OVX + BCA (5 mg/kg), OVX + BCA (20 mg/kg), OVX + BCA (60 mg/kg), and OVX + estradiol (E2; 0.35 mg/kg), which were administrated daily by gavage for 12 weeks. Learning and memory were examined using the Morris water-maze test before the end of the experiment. Morphological changes of the rat hippocampus were observed by HE staining and electron microscopy. Malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) in the hippocampus were measured. The effect of BCA on cell viability was measured in the presence of hydrogen peroxide (H2O2) using CCK8. Flow cytometry was used to measure neuronal apoptosis and reactive oxygen species (ROS) induced by H2O2. Expression of Bcl-2, Bax, and Caspase-3 was determined by Western blotting using hippocampal tissues and primary cultures of hippocampal neurons. Results: Chronic treatment with BCA mimicked the ability of E2 to reverse the deficit of learning and memory in the Morris water-maze test in OVX rats. BCA normalized OVX-induced morphological changes as revealed by HE staining and electron microscopy. In addition, BCA significantly decreased the levels of MDA, the biomarker of oxidative damage, and increased the activity of the intracellular antioxidant enzymes SOD and GSH-Px in OVX rats. Further, in primary cultures of hippocampal neurons, BCA reversed H2O2-induced decreases in cell viability and accumulation of ROS. Finally, BCA reversed OVX- or H2O2-induced increases in Bax and Caspase-3 and decreases in Bcl-2 in the hippocampus and primary cultures of hippocampal neurons. Conclusion: These results suggest that BCA improves memory through its neuroprotective properties in the brain under the circumstance of estrogen deficiency and can be used for treatment of memory loss in postmenopausal women.
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Affiliation(s)
- Yanmeng Zhou
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Bingbing Xu
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Haiyang Yu
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Wei Zhao
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Xinxin Song
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Yan Liu
- The Second Affiliated Hospital of Shandong First Medical University, Taian, China
| | - Kainan Wang
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Nikoli Peacher
- Departments of Neuroscience and Behavioral Medicine and Psychiatry, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United States
| | - Xiaomin Zhao
- Institute of Pharmacology, Shandong First Medical University and Shandong Academy of Medical Sciences, Taian, China
| | - Han-Ting Zhang
- Departments of Neuroscience and Behavioral Medicine and Psychiatry, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, United States
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15
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Wang BN, Wu CB, Chen ZM, Zheng PP, Liu YQ, Xiong J, Xu JY, Li PF, Mamun AA, Ye LB, Zheng ZL, Wu YQ, Xiao J, Wang J. DL-3-n-butylphthalide ameliorates diabetes-associated cognitive decline by enhancing PI3K/Akt signaling and suppressing oxidative stress. Acta Pharmacol Sin 2021; 42:347-360. [PMID: 33462377 PMCID: PMC8027654 DOI: 10.1038/s41401-020-00583-3] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Accepted: 11/16/2020] [Indexed: 02/07/2023]
Abstract
DL-3-n-Butylphthalide (DL-NBP), a small molecular compound extracted from the seeds of Apium graveolens Linn (Chinese celery), has been shown to exert neuroprotective effects due to its anti-inflammatory, anti-oxidative and anti-apoptotic activities. DL-NBP not only protects against ischemic cerebral injury, but also ameliorates vascular cognitive impairment in dementia patients including AD and PD. In the current study, we investigated whether and how DL-NBP exerted a neuroprotective effect against diabetes-associated cognitive decline (DACD) in db/db mice, a model of type-2 diabetes. db/db mice were orally administered DL-NBP (20, 60, 120 mg· kg-1· d-1) for 8 weeks. Then the mice were subjected to behavioral test, their brain tissue was collected for morphological and biochemical analyses. We showed that oral administration of DL-NBP significantly ameliorated the cognitive decline with improved learning and memory function in Morris water maze testing. Furthermore, DL-NBP administration attenuated diabetes-induced morphological alterations and increased neuronal survival and restored the levels of synaptic protein PSD95, synaptophysin and synapsin-1 as well as dendritic density in the hippocampus, especially at a dose of 60 mg/kg. Moreover, we revealed that DL-NBP administration suppressed oxidative stress by upregulating Nrf2/HO-1 signaling, and increased brain-derived neurotrophic factor (BDNF) expression by activating PI3K/Akt/CREB signaling in the hippocampus. These beneficial effects of DL-NBP were observed in high glucose-treated PC12 cells. Our results suggest that DL-NBP may be a potential pharmacologic agent for the treatment of DACD.
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Affiliation(s)
- Bei-Ni Wang
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Cheng-Biao Wu
- Research Center, Affiliated Xiangshan Hospital, Wenzhou Medical University, Ningbo, 315700, China
| | - Zi-Miao Chen
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Pei-Pei Zheng
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Ya-Qian Liu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jun Xiong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Jing-Yu Xu
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, 325035, China
| | - Pei-Feng Li
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
| | - Abdullah Al Mamun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Li-Bing Ye
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Zhi-Long Zheng
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yan-Qing Wu
- The Institute of Life Sciences, Engineering Laboratory of Zhejiang province for Pharmaceutical Development of Growth Factors, Biomedical Collaborative Innovation Center of Wenzhou, Wenzhou University, Wenzhou, 325035, China.
| | - Jian Xiao
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325000, China.
| | - Jian Wang
- Department of Hand Surgery and Peripheral Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
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